Nitrate salt of anti-ulcer medicine

ABSTRACT

Nitrate salt compositions with anti-ulcer medicines having formula (A) and (B) wherein the (A) class compounds: R=H, OCH 3 , OCHF 2 ; R 1 =CH 3 , OCH 3 ; R 2 =H, CH 3 ; R 3 =CH 3 , CH 2 —CF 3 , (CH 2 ) 3 —OCH 3 ; wherein the (B) class compounds: R I   3 , R I   4  equal to or different from each other, are respectively free valence hydrogen, (1), —CH 2 —N(CH 3 ) 2 ; Y=S, N—R I   6 , CR I   7 R I   8 ; X=O, S, N—R I   1 ; R I   2 =H, CH 3 ; n=0, 1; Z=N—CN, N—SO 2 NH 2 , CH—NO 2  or formula (VII A ) R I   5 =H, —NH—CH 3 , NH 2 ; R I   6 , R I   7 , R I   8 , R I   1 , equal to or different from each other, are hydrogen, free valence. The invention also comprises the methods for the preparation of above salts.

The present invention relates to compositions to be used in the therapyand in the prevention of the ulcer relapses and, in general, ofdyspepsias. More particularly it relates to compositions having animproved gastroprotective activity combined with a high acid secretioninhibition activity.

Products known in the art and those commercialized and used in the ulcertherapy are compounds which perform an anti-secretory activity (acidsecretion inhibition). See for instance “New Guide to Medicine & Drugs”Brit. Medical Assoc. Editor, 1997, pagg. 108-109. Known products havinghigher therapeutic efficacy show a high anti-secretory activity and areused, both in the acute and in long-therm (six months and more)therapies. The drawback of these products is that they have a poorgastroprotectve activity, when present. From a practical point of viewthis means that the gastric protection is not optimal and causesinconveniences above all in the long-term therapy. In this case thepresence of frequent relapses due to the enfeeblement of gastric mucosais noticed.

To overcome these inconveniences it is known in the art to add to abovemedicines other anti-ulcer medicines having a gastroprotective action:prostaglandins, bismuth salts (e.g. bismuth citrate) and antibiotics. Insuch way the remission of ulcerous pathology is achieved. However abovecombinations are not satisfactory as for their tolerability in general.For example it is well known that prostaglandins produce side effects(diarrhoea) towards the intestinal tract; bismuth salts frequentlyproduce nausea and gastric burning. Antibiotics produce unwantedgastrointestinal effects.

The need was felt to have available compositions active in the ulcer andgastric dyspepsia treatment, having improved therapeutic characteristicand tolerability, general and local, in particular having an improvedgastroprotective activity combined to a high anti-secretion activity.

The Applicant has unexpectedly and surprisingly found pharmaceuticalanti-ulcer compositions having the above mentioned desired properties.

It is an object of the present invention pharmaceutical compositionscomprising as essential components nitrate salts of one or morecomponents selected from the following classes of compounds:

where in the (A) class compounds:

R=H, OCH₃, OCHF₂;

R₁=CH₃, OCH₃;

R₂=H, CH₃;

R₃=CH₃, CH₂—CF₃, (CH₂)₃—OCH₃;

where in the class (B) compounds:

R^(I) ₃, R^(I) ₄ equal to or different from each other, are respectivelyfree valence, hydrogen —N=C(NH₂)₂, —CH₂—N(CH₃)₂;

Y=S, N—R^(I) ₆, CR^(I) ₇R^(I) ₈;

X=O, S, N—R^(I) ₁;

R^(I) ₂=H, CH₃;

n=0, 1;

Z=N—CN, N—SO₂NH₂, CH—NO₂ or

R^(I) ₅=H, —NH—CH₃, NH₂;

R^(I) ₆, R^(I) ₇, R^(I) ₈, R^(I) ₁, equal to or different from eachother, are hydrogen, free valence.

The preferred nitrate salts with the (A) formula precursors are thefollowing:

when R=OCH₃, R₁=CH₃, R₂=CH₃, R₃=CH₃, Omeprazole residue; as inOmeprazole, but with R=OCHF₂, R₁=OCH₃, R₂=H, Pantoprazole residue;

as in Omeprazole, but with R=H, R₂=H, R₃=(CH₂)₃—OCH₃, Rabeprazoleresidue;

as in Rabeprazole, but with R₃=CH₂—CF₃, Lansoprazole residue.

In the (A) class compounds also those having the followingintramolecular ring are comprised, obtainable by treating the precursorsin an acid aqueous environment (rif. “A Textbook of Drug Design andDevelopment”, Harwood Academic Publisher,1991, pag. 140):

wherein N^(AI) and C^(AII) mean, respectively, the nitrogen and carbonatom in 1 and 2 position of the pyridine ring of formula A and C^(B2)and N^(B3) the carbon and nitrogen atom, respectively, in 2 and 3position of the imydazole ring (1 position of the imydazole ring is thatof the proton nitrogen).

The preferred nitrate salts with the (B) formula precursors are thefollowing:

when in (B) formula X=N—R^(I) ₁, with R^(I) ₁ free valence, Y=N—R^(I) ₆with R^(I) ₆=H, R^(I) ₃=H, R^(I) ₄ is a free valence and forms withR^(I) ₁ a double bond, R^(I) ₂=CH₃, n=1, R^(I) ₅=NH—CH₃, Z=N—CN,Cimetidine residue;

when X=N—R^(I) ₁ with R^(I) ₁ free valence, Y=S, R^(I) ₃=—N=C(NH₂)₂,R^(I) ₄ is a free valence and forms with R^(I) ₁ a double bond, R^(I)₂=H, n=1 R^(I) ₅=H, Z=(VII_(A)), Ebrotidine residue;

as in Ebrotidine but with n=0, R^(I) ₅=NH₂ and Z=N—SO₂NH₂, Famotidineresidue;

as in Ebrotidine but with R^(I) ₃=—CH₂—N(CH₃)₂, R^(I) ₅=—NH—CH₃ andZ=CH—NO₂, Nizatidine residue;

as in Nizatidine, but with X=oxygen, Y=CR^(I) ₇R^(I) ₈ with R^(I) ₇hydrogen and R^(I) ₈ free valence, R^(I) ₄ is a free valence and formswith R^(I) ₈ a double bond, Ranitidine residue.

In the compositions according to the present invention also opticalisomers of the compounds belonging to (A) and (B) classes may be used.

In the compositions according to the present invention the compoundsalts of above classes contain at least one mole of nitrate ion/mole ofcompounds. Preferably the ratio between the nitrate ion moles and theprecursor is equal to one. Salts having a higher molar ratio areobtained when in the molecule other amino groups basic enough to besalified are present.

Salt precursors belonging to the above mentioned classes are preparedaccording to the methods described in “The Merck Index 12^(a) Ed.”(1996), herein completely incorporated by reference.

The salts of the present invention may be prepared according to one ofthe following methods.

When the substance to be salified is available as free base or as asoluble corresponding salt in an organic solvent, which preferably doesnot contain hydroxyl groups, for example acetonitrile, ethyl acetate,tetrahydrofuran ecc., the salt is prepared by dissolving the substancein the solvent at a concentration preferably equal or higher than 10%w/v, by adding the amount of concentrated nitric acid corresponding tothe moles of salifiable aminic groups present in the compound. Thenitric acid is preferably diluted in the same solvent. Preferably duringand after the addition the mixture is cooled to temperatures in therange 20°-0° C. The product is generally recovered by filtration andwashed with the solvent.

When on the contrary the substance is not much soluble or it isavailable as a not much soluble salt in the above mentioned solvents,the corresponding mixtures with hydroxylated solvents may be used.Examples of such solvents are methyl alcohol, ethyl alcohol and water.The precipitation can be quickened by diluting then the so obtainedmixture, after the addition of nitric acid, with an apolar solvent.

When the starting product is salified with hydrochloric acid it ispossible to prepare the salt with nitric acid directing adding silvernitrate to the compound solution. After filtering silver chloride, thesolution is concentrated and cooled to recover the nitrate salt.

When the starting product is a salt, it is possible to liberate thecorresponding base by a treatment with a sodium or potassium carbonateor bicarbonate saturated solution, or with a sodium or potassiumhydroxide diluted solution. The base is then extracted by a suitableorganic solvent (e.g. halogenated solvents, esters, ethers) which isthen dried. The organic solution is evaporated and then one proceedsaccording to the preceding preparation methods, by dissolving the basein acetonitrile or in the other above mentioned solvents.

It has now surprisingly been found that the compositions of the presentinvention allow to improve, compared with the known above mentionedcombinations, the comprehensive pharmaco-toxicological situation ofprecursors, increasing the therapeutic efficacy and their general andlocal tolerability in the ulcer and gastric dyspepsia treatment with animproved gastroprotective activity.

The compositions of the present invention are formulated in thecorresponding pharmaceutical compositions according to well knowntechniques in this field together with the common excipients; see forexample the volume “Remington's Pharmaceutical Sciences 15a Ed.”

The invention salt dosages are the conventional ones of their precursorsof (A) and (B) classes.

It is a further object of the present invention the compositionsobtainable combining one or more nitrate salts of the compounds of (A)and (B) classes, or their pharmaceutical compositions, with conventionalgastroprotectives. As examples, prostaglandines, bismuth salts, activeantibiotics towards pathogenic microorganisms in the gastrointestinalmucosa can be mentioned. It has surprisingly been found thatgastroprotective activity of the invention compositions is very high.This makes it possible to avoid the undesirable effects of knowngastroprotectives when they are used in combination with compounds orformulation of the invention. It has indeed been found that the amountof known gastroprotectives, in the combination of the invention, islower compared with those known and does not cause undesirable effects.The skilled in this field is able to easily determine the maximum amountof conventional gastroprotectives to be combined with the pharmaceuticalcompositions of the invention since this corresponds to the absence oftypical side effects of known gastroprotectives. In any case the amountof conventional gastroprotectives to be used in the combination is lowerthan that used in the combinations described in the art.

The following examples have the purpose to illustrate the invention andmust not be considered as limitative of the same.

EXAMPLE 1 Preparation of Cimetidine Nitrate Salt

10 g of cimetidine are dissolved in 100 ml of anacetonitrile/tetrahydrofuran/water 1:1:2 (composition by volume) mixturecooled at +4° C. 10 ml acetonitrile solution containing 2.5 ml of 70%nitric acid are added little by little. The solution is diluted withethyl ether, maintaining the temperature at +40° C., till to incipientprecipitation of the product. After a some hour rest the precipitatedsolid is filtered, washed with ethyl ether and dried. 12.1 g ofcimetidine mononitrate salt are recovered having m.p. 158°-159° C. (withdecomposition).

¹H—NMR (D₂O): 8,55 (1H, s), 3,83 (2H, S), 3,32 (2H, s), 2,77 (3H, s),2,68 (2H, t), 2,32 (3H, s). Elementary analysis:

calc. (%) C 38.09 H 5.43 N 31.09 S 10.17 found (%) C 37.99 H 5.41 N31.16 S 10.25

Example 2 Preparation of Ranitidine Nitrate Salt

5 g of ranitidine hydrochloride are dissolved in a 140 mlacetonitrile/methyl alcohol 6:1 mixture at +20° C. 4,2 g of powdersilver nitrate are added. The silver chloride precipitate is filtered,the precipitate is washed with an acetonitrile/methyl alcohol 6:1solution, the organic phases are put together, dried and treated toobtain a dry residue. 3,5 g of an amorphous solid corresponding to theranitidine mononitrate salt are obtained.

¹H—NMR (D₂O) :6,70 (1H, d), 6,40 (1H, d), 4,34 (2H, s), 3,83 (2H, s),3,43 (2H, t), 2,93 (2H, m), 2,87 (9H, s).

calc. (%) C 41.37 H 6.14 N 18.56 S 8.50 found (%) C 41.12 H 6.20 N 18.44S 8.38

PHARMACOLOGICAL TESTS

Example 3 Acute Toxicity

A single dose equal to 100 mg/Kg respectively of cimetidine andranitidine nitrate salts, delt with in the previous Examples, has beengiven to a group of 10 rats weighing 20 g each by a cannula by oral wayin a carboxymethylcellulose aqueous suspension 2% w/v.

The animals are kept under observation for 14 days. In no one of thegroup animals the toxic symthom presence was noted.

Example 4 Anti-ulcer Activity

Anti-ulcer activity is evaluated according to the experimental modeldescribed in the paper of A. Robert e Al. “Cytoprotection byprostaglandins in rats. Prevention of gastric necrosis produced byalcohol, HCl, NaOH, hypertonic NaCl and thermal injury” 77, 433-43 1979.

To 5 groups of 10 rats each, kept on empty stomach since the previousnight, 15 minutes before the supply of absolute ethyl alcohol (1 ml), byoral way are supplied:

5 ml/Kg of carboxymethylcellulose aqueous suspension 2%.

50 mg/Kg of cimetidine in 5 ml/Kg of carboxymethylcellulose aqueoussuspension 2%.

62,5 mg/Kg of cimetidine nitrate (corresponding to 50 mg/Kg ofcimetidine) in 5 ml/Kg of carboxymethylcellulose aqueous suspension 2%.

50 mg/Kg of ranitidine in 5 ml/Kg of carboxymethylcellulose aqueoussuspension 2%.

60 mg/Kg of ranitidine nitrate (corresponding to 60 mg/Kg of ranitidine)in 5 ml/Kg of carboxymethylcellulose aqueous suspension 2%.

A hour later the animals are sacrificed and the gastric lesion incidenceis evaluated. Results are reported in Table 1 and they show thatcimetidine and ranitidine nitrate salts have an improvedgastroprotective activity compared with the corresponding startingproducts.

TABLE I Gastric Damage Treatment % Vehicle 100 Cimetidine 100Cimetidine.HNO₃ 50 Ranitidine 80 Ranitidine.HNO₃ 40

What is claimed is:
 1. A nitrate salt of a compound chosen from thefollowing classes:

where in the compounds of formula (A): R=OCH₃, R₁=CH₃, R₂=CH₃, R₃=CH₃;R=OCHF₂, R₁=OCH₃, R₂=H, R₃=CH₃; R=H, R₁=CH₃, R₂=H, R₃=(CH₂)₃—OCH₃; R=H,R₁=CH₃, R₂=H, R₃=CH₂—CF₃;  where in formula (B): X=N—R^(I) ₁ with R^(I)₁ free valence, Y=N—R^(I) ₆ with R^(I) ₆=H, R^(I) ₃=H, R^(I) ₄ is a freevalence and forms with R^(I) ₁ a double bond, R^(I) ₂=CH₃, n=1, R^(I)₅=—NH—CH₃, Z=N—CN; X=N—R^(I) ₁ with R^(I) ₁ free valence, Y=S, R^(I)₃=—N=C(NH₂)₂, R^(I) ₄ is a free valence and forms with R^(I) ₁ a doublebond, R^(I) ₂=H, n=1, R^(I) ₅=H, Z=(VII_(A)):

X=N—R^(I) ₁ with R^(I) ₁ free valence, Y=S, R^(I) ₃=—N=C(NH₂)₂, R^(I) ₄is a free valence and forms with R^(I) ₁ a double bond, R^(I) ₂=H, n=0,R^(I) ₅=NH₂ and Z=N—SO₂NH₂; X=N—R^(I) ₁ with R^(I) ₁ free valence, Y=S,R^(I) ₃=—CH₂—N(CH₃)₂, R^(I) ₄ is a free valence and forms with R^(I) ₁ adouble bond, R_(I) ₂=H, n=1, R^(I) ₅=—NH—CH₃, Z=CH—NO₂; X=oxygen,Y=CR^(I) ₇R^(I) ₈ with R^(I) ₇ hydrogen and R^(I) ₈ fee valence, R^(I)₃=—CH₂—N(CH₃)₂, R^(I) ₄ is a free valence and forms with R^(I) ₇ adouble bond, R^(I) ₂=H, n=1, R^(I) ₅=—NH—CH₃, Z=CH—NO₂.
 2. A nitratesalt of an optical isomer of a compound according to claim
 1. 3. Apharmaceutical composition containing an effective amount of a nitratesalt according to claim 1 together with excipients and/or carriers.
 4. Amethod of treating ulcers and gastric dyspepsia, said method comprisingadministering to a patient in need thereof an effective amount of thenitrate salts according to claim
 1. 5. A composition containing anitrate salt according to claim 1 together with conventionalgastroprotective drugs.
 6. Compositions according to claim 5 whereinconventional gastroprotectives are selected from prostaglandins, bismuthsalts and antibiotics.
 7. A method for treating ulcers and gastricdyspepsias, said method comprising administering to a patient in needthereof an effective amount of the composition of claim
 5. 8. A methodfor the preparation of nitrate salts according to claim 1, wherein whenthe substance to be salified is available as free base or as a solublecorresponding salt in an organic solvent which does not contain hydroxylgroups the salt is prepared by dissolving the substance in the solventat a concentration equal or higher than 10% w/v, by adding the amount ofconcentrated nitric acid corresponding to the moles of salifiable aminicgroups present in the compound, by cooling during and after the additionat temperatures in the range 20° C.-0° C. and by recovering the productby filtration; wherein when the starting material is salified withhydrochloric acid, the salt with nitric acid is prepared by directlyadding silver nitrate to the compound solution, by filtering the silverchloride; the solution is then concentrated and cooled to recover thenitric salt.
 9. A method for the preparation of nitrate salts accordingto claim 1, wherein when the starting product is a salt, thecorresponding base is liberated by a treatment with a sodium orpotassium carbonate or bicarbonate saturated solution or with a sodiumor potassium hydroxide diluted solution, by extracting the base with asuitable organic solvent, and when the substance to be salified isavailable as free base or as a soluble corresponding salt in an organicsolvent which does not contain hydroxyl groups the salt is prepared bydissolving the substance in the solvent at a concentration equal orhigher than 10% w/v, by adding the amount of concentrated nitric acidcorresponding to the moles of salifiable aminic groups present in thecompound, by cooling during and after the addition at temperatures inthe range 20° C.-0° C. and by recovering the product by filtration. 10.A pharmaceutical composition containing an effective amount of acomposition according to claim 5 together with excipients and/orcarriers.
 11. The method according to claim 9, wherein when thesubstance is not much soluble or it is available as a not much solublesalt in the solvent containing hydroxyl groups, the correspondingmixtures with hydroxylated solvents are used and the precipitation isquickened by diluting the so obtained mixture, after the addition ofnitric acid, with an apolar solvent.